Progesterone utility in the synthesis of steroidal heterocyclic compounds with antitumor activity

One–pot and efficient method for the synthesis of progesteronpyridine 5a-c, 6a-c and 7a,b and/or progesteronpyran derivatives 9a-c and 10a,b by condensation reaction of progesterone 1 with different aldehydes and active methylene compounds in the presence of ammonium acetate or piperidine.  New progesteronopyrimidine derivatives 12a-d and 13a, b were synthesized via interaction of progesterone 1 with urea or thiourea and/or guanidine reagents and aldehyde. Progesterone 1 was examined to synthesize heterocyclic compound 16 containing ?-Lactone chiral carbon via the reaction of hydrazone derivative 14 with phenyl isothiocyanate followed by boiling with chloroacetic acid in benzene. The biological activity of compounds 5a, 5b, 6b, 7a, 9b, 9c, 12a, 12c, and 13a were evaluated as growth inhibitors of the liver and the breast carcinoma human cell line (HEPG2 & MCF7). Compounds 13a, 12a and 7a showed a higher potency than the standard. Key Words: Progesterone, MCR’s (multicomponents reaction), (pyridine, pyran, pyrimidine, ?-Lactone) derivatives, HEPG2 & MCF7

MIR-99a and MIR-99b Modulate TGF-β Induced Epithelial to Mesenchymal Plasticity in Normal Murine Mammary Gland Cells

Epithelial to mesenchymal transition (EMT) is a key process during embryonic development and disease development and progression. During EMT, epithelial cells lose epithelial features and express mesenchymal cell markers, which correlate with increased cell migration and invasion. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that induces EMT in multiple cell types. The TGF-β pathway is regulated by microRNAs (miRNAs), which are small non-coding RNAs regulating the translation of specific messenger RNAs

The EYA Tyrosine Phosphatase Activity Is Pro-Angiogenic and Is Inhibited by Benzbromarone

Eyes Absents (EYA) are multifunctional proteins best known for their role in organogenesis. There is accumulating evidence that overexpression of EYAs in breast and ovarian cancers, and in malignant peripheral nerve sheath tumors, correlates with tumor growth and increased metastasis. The EYA protein is both a transcriptional activator and a tyrosine phosphatase, and the tyrosine phosphatase activity promotes single cell motility of mammary epithelial cells. Since EYAs are expressed in vascular endothelial cells and cell motility is a critical feature of angiogenesis we investigated the role of EYAs in this process. Using RNA interference techniques we show that EYA3 depletion in human umbilical vein endothelial cells inhibits transwell migration as well as Matrigel-induced tube formation. To specifically query the role of the EYA tyrosine phosphatase activity we employed a chemical biology approach. Through an experimental screen the uricosuric agents Benzbromarone and Benzarone were found to be potent EYA inhibitors, and Benzarone in particular exhibited selectivity towards EYA versus a representative classical protein tyrosine phosphatase, PTP1B. These compounds inhibit the motility of mammary epithelial cells over-expressing EYA2 as well as the motility of endothelial cells. Furthermore, they attenuate tubulogenesis in matrigel and sprouting angiogenesis in the ex vivo aortic ring assay in a dose-dependent fashion. The anti-angiogenic effect of the inhibitors was also demonstrated in vivo, as treatment of zebrafish embryos led to significant and dose-dependent defects in the developing vasculature. Taken together our results demonstrate that the EYA tyrosine phosphatase activity is pro-angiogenic and that Benzbromarone and Benzarone are attractive candidates for repurposing as drugs for the treatment of cancer metastasis, tumor angiogenesis, and vasculopathies

Cross-border trafficking in human beings: prevention and intervention strategies for reducing sexual exploitation

Over the years, growing attention has been given to the phenomenon of trafficking in human beings (THB). Sexual exploitation was until recently by far the most commonly identified feature of THB, followed by forced labour. Many activities to combat trafficking for the purpose of sexual exploitation have been initiated by numerous supranational, international as well as national organizations. Much is written about these initiatives, but some areas have been neglected. Knowledge on ‘what works’ is in particular limited. The growing attention to THB entails a demand for more information. The severity of the crime and the impact on its victims makes it of utmost importance to gain more insight into the working and effectiveness of anti-trafficking strategies and interventions. The main objective of this review was to assess the presently available evidence on the effects of interventions that aim to prevent and suppress trafficking in human beings

The Maule (Chile) Earthquake of February 27, 2010: Consequence Assessment and Case Studies

On February 27, 2010 at 03:34 am local time, a powerful earthquake of magnitude 8.8 struck central Chile. The epicenter of the earthquake was approximately 8 km off the central region of the Chilean coast. With an inclined rupture area of more than 80,000 square km that extends onshore, the region of Maule was subjected to a direct hit, with intense shaking of duration of at least 100 seconds, and peak horizontal and vertical ground acceleration of over 0.6 g. The earthquake caused the death of 521 persons, with almost half of the fatalities caused by the consequential tsunami. Over 800,000 individuals were directly affected through death, injury and displacement. More than a third of a million buildings were damaged to varying degrees, including several cases of total collapse of major structures. The transportation system was dealt a crippling blow, with 830 failures registered with the Ministry of Public Works on roads in both the public and private transportation networks. Disruption of commerce as well as the rescue and response effort resulted from the damage to roads, embankments and bridges. On the whole, the performance of engineered structures was reasonable, taking into account the magnitude and proximity of the earthquake. The latter conclusion is supported by the observations from several back-analyses presented in this report. Damage to non-engineered construction is as expected in major earthquakes. Most reinforced concrete bridges behaved well. The role of social networking tools in enabling the affected population to communicate was a most interesting feature in the response to this earthquake. Due to the failure of the power grid, and the congestion of the cellphone network, the population resorted to short message service and web social media. Ham radio networks were activated to fill gaps due to the failure of the radio network in places. The failure in ham radio broadcast in coastal regions might have increased the fatalities because tsunami warning did not reach all hazardous locations. The MAE Center field reconnaissance team members consider that Chilean engineering was proven to be robust and that seismic design provisions and construction practices are of high standard. The extensive damage from this Mw = 8.8 earthquake is expected and within the ???life safety??? performance target of seismic design codes.National Science Foundation EEC-9701785unpublishednot peer reviewe

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